CN1717397A - 1,2,4-triazole derivative, method for preparing the same, and pharmaceutical composition containing the same - Google Patents
1,2,4-triazole derivative, method for preparing the same, and pharmaceutical composition containing the same Download PDFInfo
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- CN1717397A CN1717397A CNA038256940A CN03825694A CN1717397A CN 1717397 A CN1717397 A CN 1717397A CN A038256940 A CNA038256940 A CN A038256940A CN 03825694 A CN03825694 A CN 03825694A CN 1717397 A CN1717397 A CN 1717397A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
A 1,2,4-triazole derivative of formula 1 or a non-toxic salt thereof, a preparation method thereof, and a pharmaceutical composition containing the derivative or the salt as an active ingredient are provided.
Description
Technical field
The present invention relates to 1,2,4-triazole derivative or its non-toxic salt, its preparation method and contain the pharmaceutical composition of described compound as activeconstituents.
Background technology
The effect of most of non-steroid class anti-inflammatory agenies is that enzyme, cyclo-oxygenase (COX) or PGG/H synthase are blocked, to reduce inflammation, pain or fever.In addition, the uterine contraction that their inhibition are caused by hormone, and the growth that also suppresses several cancers.Cyclo-oxygenase-1 (COX-1) is at first found in bovid.COX-1 can be in the various kinds of cell type constitutive expression.Different with COX-1, cyclooxygenase-2 (COX-2) is the isotype of the cyclo-oxygenase of recent findings, can easily be produced by mitogen, intracellular toxin, hormone, somatomedin or cytokine induction.
Prostaglandin(PG) is various pathology and the important amboceptor of physiological process.COX-1 plays the important physical effect, as discharge endogenous prostaglandin(PG), safeguard the form of stomach and function, and the blood circulation of kidney.On the other hand, produce COX-2 by inflammatory factor, hormone, somatomedin or cytokine induction.Therefore different with composing type COX-1, COX-2 is relevant with the pathologic process of prostaglandin(PG).On this point, according to mechanism of action and conventional non-steroid class anti-inflammatory agent relatively, the less generation of the selective depressant of COX-2 or have side effects hardly.In addition they reduce inflammation, pain and fever, and suppress the uterine contraction that causes by hormone and the growth of several cancers.Particularly they can reduce side effect such as stomach toxicity and renal toxicity effectively.Further, they suppress the synthetic of contractile prostanoid, thereby can suppress the contraction of unstriated muscle.Therefore, they help prevent premature, irregular menses, asthma and eosinocyte disease.
The non-steroid class anti-inflammatory agent of report is at treatment large bowel cancer [European Journal of Cancer, Vol37, p2302,2001], prostate cancer [Urology recently, Vol 58, p127,2001] and dull-witted [Exp.Opin.Invest.Drugs, Vol 9, p671,2000] aspect is effective.
In addition, the selective depressant of expection COX-2 is effective to treatment osteoporosis and glaucoma.There is report to describe purposes [the John Vane: " Towards a Better Aspirin ", nature (Nature), Vol.367, pp215-216,1994 of the selective depressant of COX-2 in detail; BrunoBattistini, Regina Botting and Y.S.Bakhle: " COX-1 and COX-2:Toward theDevelopment of More Selective NSAIDs ", drug information and prospect (Drug News andPerspectives), Vol.7, pp501-512,1994; David B.Reitz and Karen Seibert, " Selective Cyclooxygenase Inhibitors ", medical chemistry annual report (Annual Reports inMedicinal Chemistry), James A.Bristol edits, Vol.30, pp179-188,1995].
Various selective COX-2-2 inhibitor have been understood with different structure.Among them, a kind of have the selective COX-2 that the diaryl heterocycle structure is a tricyclic structure-2 inhibitor and obtained extensive studies as strong material standed for.This diaryl heterocycle structure has a center ring and the sulfamoyl group or the methylsulfonyl group that are connected on one of them aromatic ring.A kind of material that has this diaryl heterocycle structure at first is Dup697[Bioorganic ﹠amp; Medicinal Chemistry Letters Vol5, p2123,1995].From that time, found to have the SC-58635 (Journal ofMedicinal Chemistry, Vol 40, p1347,1997) of pyrazoles ring and had the MK-966 (WO95/00501) of furanone ring, they are derivatives of Dup697.
The Celecoxib of formula 42 is U.S. Patent numbers 5,466, disclosed a kind of selective COX-2-2 inhibitor in 823.This Celecoxib is a kind of pyrazolyl benzenesulfonamide derivatives of replacement.
Formula 42
Disclose the Rofecoxib of formula 43 among the WO95/00501, it is another kind of selective COX-2-2 inhibitor.This Rofecoxib has the diaryl heterocycle structure of band center furanone ring.
Formula 43
U.S. Patent number 5,633, the Valdecoxib of disclosed formula 44 is another selective COX-2-2 inhibitor in 272.This Valdecoxib has benzsulfamide part and a center isoxazole ring.
Formula 44
The selective COX-2 of formula 42～44-2 inhibitor is effective inflammation treatment agent, and is less or almost be free from side effects with their side effect of the non-steroid class of routine anti-inflammatory agent comparison.
Summary of the invention
An object of the present invention is to provide 1,2 of formula 1,4-triazole derivative or its non-toxic salt.
Another object of the present invention provides preparation 1,2, the method for 4-triazole derivative or its non-toxic salt.
Another purpose of the present invention provide be used for the treatment of fever, pain and inflammation contain 1,2,4-triazole derivative or its non-toxic salt are as the pharmaceutical composition of activeconstituents.
A further object of the present invention provides and is used for the treatment of cancer and dull-witted contains 1,2, and 4-triazole derivative or its non-toxic salt are as the pharmaceutical composition of activeconstituents.
Implement best mode of the present invention
According to an aspect of the present invention, provide by 1,2 of formula 1 expression 4-triazole derivative or its non-toxic salt:
Formula 1
Wherein, Ar represents naphthyl; 3, the 4-methylenedioxyphenyl; Phenyl; Or by being selected from C
1-C
6Alkyl, C
1-C
6Alkoxyl group, or the phenyl of the group of halogen replacement.
1,2 of formula 1,4-triazole derivative can non-toxic salt form exist.Term used herein " non-toxic salt " is meant that pharmacy is acceptable, does not contain the salt of toxin, comprises organic salt and inorganic salt.
1,2 of formula 1, the inorganic salt of 4-triazole derivative comprise the inorganic salt of aluminium, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium or zinc, but are not limited to these.Inorganic ammonium, calcium, potassium or sodium salt are preferred.
1,2 of formula 1, the organic salt of 4-triazole derivative comprise primary amine, secondary amine or tertiary amine, the replacement amine of nature existence or the organic amine salt of cyclammonium, or the salt of deacidite, but are not limited to these.The example of the salt of deacidite includes but not limited to arginine, trimethyl-glycine, trimethyl-xanthine, choline, N, the N-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, the N-methylglucosamine, glycosamine, glucosamine, Histidine, azanol, N-(2-hydroxyethyl) piperidines, N-(2-hydroxyethyl) tetramethyleneimine, Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, the polyamines resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, the salt of tripropyl amine and Tutofusin tris.
1,2 of formula 1,4-triazole derivative can organic acid salt or the form of inorganic acid salt exist.
1 of formula 1,2, the organic acid salt of 4-triazole derivative or the example of inorganic acid salt comprise acetate, hexanodioic acid, aspartic acid, 1, the 5-naphthalene disulfonic acid, disulfonic acid, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, 1, the 2-ethionic acid, ethyl sulfonic acid, ethylenediamine tetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, glyconic acid, L-glutamic acid, hydroiodic acid HI, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, the 2-naphthalene disulfonic acid, nitric acid, oxalic acid, pentothenic acid, phosphoric acid, PIVALIC ACID CRUDE (25), propionic acid, Whitfield's ointment, stearic acid, succsinic acid, sulfuric acid, tartrate, tosic acid, undeeanoic acid, salt with the 10-undecylenic acid.Preferred succsinic acid, Hydrogen bromide, hydrochloric acid, toxilic acid, methylsulfonic acid, phosphoric acid, sulfuric acid or tartaric salt.
The present invention is preferred 1,2, and the 4-triazole derivative comprises:
1-(3-fluoro-4-methylsulfonyl phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-p-methoxy-phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-fluorophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-bromophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-chloro-phenyl-)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-aminomethyl phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-ethoxyl phenenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3-chloro-phenyl-)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3-fluorophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3-fluoro-4-p-methoxy-phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3-aminomethyl phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(naphthalene-2-yl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
5-([1,3] benzo dioxole-5-yl)-1-(3-fluoro-4-methylsulfonyl phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole; With
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3, the 4-difluorophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole.
According to another aspect of the present invention, provide here by formula 2 expression, as 1,2 of synthesis type 1, the 1,2,4-triazol derivatives of the intermediate of 4-triazole derivative:
Formula 2
Wherein n is 0 or 2.
According to another aspect of the present invention, provide 1,2 of preparation formula 1 here, the method for 4-triazole derivative or its non-toxic salt, this method comprise that the acyl chlorides with the 1,2,4-triazol derivatives of formula 2a and formula 3 reacts in the presence of alkali.
Formula 2a
Formula 3
Wherein, Ar is suc as formula 1 definition.
According to another aspect of the present invention, provide 1,2 of preparation formula 1 here, the method for 4-triazole derivative or its non-toxic salt, this method comprise the compound that acyl chlorides reacts and oxidation produces with the 1,2,4-triazol derivatives of formula 2b and formula 3 in the presence of alkali.
Formula 2b
Above-mentioned formation 1,2, the reaction of 4-triazole is preferably carried out in polar solvent.The example of polar solvent comprises DMF, 1,4-diox, DMSO, methyl-2-pyrrolidone, or m-dimethylbenzene.
Reaction is preferably carried out under envrionment temperature to 110 ℃.Reaction times decides according to reactant.Usually, the reaction times continues 5 minutes to 36 hours.
After reaction was finished, reaction product was by adding entry and organic solvent for example ethyl acetate, methylene dichloride, and tetrahydrofuran (THF) and extracted with diethyl ether desalt to remove.This rough extract is by silica gel chromatography or use the appropriate solvent recrystallization, obtains final product.
Alkali used herein is organic bases or mineral alkali.Preferred organic bases is triethylamine, Trimethylamine, tripropyl amine, pyridine or imidazoles.Preferred mineral alkali is sodium acetate, sodium hydroxide, sodium hydride, potassium hydroxide, yellow soda ash or salt of wormwood.
Preferably in the presence of oxygenant, in methylene dichloride, finish oxidizing reaction.Preferred oxygenant is MMPP (monoperphthalic acid magnesium hexahydrate), MCPBA (m-chloroperoxybenzoic acid) or oxone (permonosulphuric acid potassium).
The compound of formula 2 can pass through the hydrazine derivative of formula 4 and the trifluoro ethanamidine (trifluoroacetimidine) of formula 5 are reacted in the presence of alkali:
Formula 4
Formula 5
Wherein n is 0 or 2.
Above-mentioned reaction is preferably carried out in THF and methyl alcohol or ethanol mixed solvent.
Reaction is preferably carried out under envrionment temperature to 66 ℃.Reaction times is determined according to reactant.Usually, the needed reaction times is 10 minutes～24 hours.
After reaction was finished, water and organic solvent washing resultant of reaction removed and desalt organic solvent such as ethyl acetate, methylene dichloride, tetrahydrofuran (THF) and ether.This rough extract obtains final product by silica gel chromatography.
Alkali used herein is organic bases or mineral alkali.Preferred organic bases is triethylamine, Trimethylamine, tripropyl amine, pyridine or imidazoles.Preferred mineral alkali is sodium acetate, sodium hydroxide, sodium hydride, potassium hydroxide, yellow soda ash or salt of wormwood.
After all described reactions are finished, can separate and the purification reaction product by the conventional chromatogram of using of this association area, recrystallization or any other method.
The method of preparation formula 1 compound can be by following reaction scheme 1 continuous representation:
Reaction scheme 1
Wherein n is 0 to 2 integer, and Ar is suc as formula 1 definition.
The described hydrazine derivative of formula 4 is prepared hydrochloride or free form according to following reaction scheme 2 or 3:
Reaction scheme 2
Reaction scheme 3
In reaction scheme 2, with 1,2-two fluoro-4-oil of mirbane and sulfo-sodium methylate prepared in reaction 2-fluoro-1-methylthio group-4-oil of mirbane.The preferred non-polar solvent that uses in routine of reaction is NMP for example, DMF, and DMSO carries out in THF or its mixed solution.More preferably use DMF/THF (1/10).Described reaction preferably in envrionment temperature to carrying out between the boiling point.Carry out if be reflected under the boiling point, reactant can reflux.
In reaction scheme 3, with 1,2-two fluoro-4-oil of mirbane and methyl-sulfinic acid sodium prepared in reaction 2-fluoro-1-methylsulfonyl-4-oil of mirbane.The non-polar solvent that described reaction is preferably used in routine is NMP for example, DMF, and DMSO carries out in THF or its mixed solution.More preferably use DMF/THF (1/10).Described reaction preferably in envrionment temperature to carrying out between the boiling point.Carry out if be reflected under the boiling point, reactant can reflux.
In reaction scheme 2 and 3, the reduction of nitrobenzene reaction can be carried out with conventional sodium borohydride/nickel chloride hexahydrate, Pd/C, the Fe etc. that use of association area.
In reaction scheme 2 and 3, phenylhydrazine can prepare with disclosed method among the EP1104760A1.
Reaction conditions for example the consumption of reaction solvent, alkali, reactant might not be limited to recited above those, can revise above-mentioned condition in conjunction with the disclosed method of the public publication of association area.
According to another aspect of the present invention, a kind of pharmaceutical composition for the treatment of fever, pain and inflammation is provided here, said composition comprises as 1,2 of the formula 1 of the treatment significant quantity of activeconstituents, 4-triazole derivative or its non-toxic salt and pharmaceutically acceptable carrier.
This pharmaceutical composition contains formula 1 compound or its non-toxic salt, and this compounds is the selective depressant of cyclooxygenase-2.Therefore this pharmaceutical composition can be used as febrifuge, analgesic agent and anti-inflammatory agent, and it has minimal side effect.
Conventional non-steroid class anti-inflammatory agent non-selectivity ground suppresses prostaglandin synthetase, cyclo-oxygenase-1 and cyclooxygenase-2.Therefore, various side effects can appear.
On the other hand, formula 1 compound and non-toxic salt thereof optionally suppress cyclooxygenase-2.Therefore can reduce the side effect that conventional non-steroid class febrifuge, analgesic agent and anti-inflammatory agent have.
Pharmaceutical composition of the present invention comprises formula 1 compound and/or its non-toxic salt and pharmaceutically acceptable carrier or vehicle.Therefore, this pharmaceutical composition can be used as the substitute of conventional non-steroid class anti-inflammatory agent.Particularly, because the reduction of the side effect of conventional non-steroid class febrifuge, analgesic agent and anti-inflammatory agent, pharmaceutical composition of the present invention are of value to the patient that treatment suffers from peptide ulceration, gastritis, regional ileitis, ulcerative colitis, diverticulitis, gastrorrhagia or hypoprothrombinemia.
Pharmaceutical composition of the present invention can be used for the whole inflammation relevant with ill prostaglandin(PG), and is particularly suitable for treating osteoarthritis and rheumatoid arthritis, and these diseases need the non-steroid class anti-inflammatory agent of high dosage.
Pharmaceutical composition of the present invention can be with the form administration of adult's dosage of formula 1 compound 1mg/ days～1000mg/ days.And the severity that can be dependent on disease is determined suitable dosage.
According to another aspect of the present invention, also provide a kind of cancer and dull-witted pharmaceutical composition of being used for the treatment of, it contains 1,2 of the formula 1 for the treatment of significant quantity, 4-triazole derivative or its non-toxic salt and pharmaceutically acceptable carrier.
Reported that recently non-steroid class anti-inflammatory agent can treat large bowel cancer [European Journal ofCancer, Vol 37, p2302,2001], prostate cancer [Urology effectively, Vol 58, p127,2001] and dull-witted [Exp.Opin.Invest.Drugs, Vol 9, p671,2000].Therefore be appreciated that pharmaceutical composition of the present invention as a kind of non-steroid class anti-inflammatory agent, also can be used for treating these diseases.
Pharmaceutical composition of the present invention can be with the form administration of adult's dosage of formula 1 compound or its non-toxic salt 1mg/ days～1000mg/ days.And the severity that can be dependent on disease is determined suitable dosage.
Pharmaceutical composition of the present invention can be with tablet, foam piece, capsule, particle, pulvis, slow releasing tablet, slow releasing capsule (single unit dosage or a plurality of unit dosage) but solution, infusion solution, suspension or the suppository form medication of intravenously and intramuscular injection, or with other dosage form medication that is fit to.
The activeconstituents that comprises in the dosage form of slow releasing pharmaceutical can contain initial dosage, also can not contain initial dosage.They are whole or in part with the slow releasing pharmaceutical dosage form of mode release of active ingredients of control.
Preferred this pharmaceutical composition is by oral administration.
This pharmaceutical composition further comprises the assistant agent of the acceptable vehicle of pharmacy and/or thinner and/or pharmacy effective dose.
The example of vehicle and assistant agent comprises gelatin; Natural sugar such as sucrose and lactose; Lecitin; Pectin; Starch such as W-Gum and amylose starch; Cyclodextrin and cyclodextrin derivative; Dextran; Polyvinylpyrrolidone; Polyvinyl acetate; Sudan Gum-arabic; Arginine (arginic acid); Wood sugar; Talcum; Whitfield's ointment; Secondary calcium phosphate; Mierocrystalline cellulose; The phthalic ester of derivatived cellulose such as methylcellulose gum, methoxy-propyl Mierocrystalline cellulose, Vltra tears and Vltra tears; Lipid acid with 12～22 carbon atoms; Emulsifying agent; Oil ﹠ fat is the vegetalitas glyceryl ester and the polyglycerol esters of saturated fatty acid particularly; Monohydroxy-alcohol; Polyvalent alcohol; Polyglycol such as polyoxyethylene glycol; Fatty alcohol with 1～20 carbon atom; Or the aliphatics with 2～22 carbon atoms is saturated or the ester of unsaturated fatty acids and polyvalent alcohol generation, polyvalent alcohol such as ethylene glycol, glycerine, glycol ether, 1,2-propylene glycol, sorbyl alcohol and N.F,USP MANNITOL.
Other assistant agent that is fit to comprises disintegrating agent.The example of disintegrating agent comprises cross-linked polyvinylpyrrolidone, carboxymethyl starch sodium salt, sodium carboxymethyl-cellulose, reaches Microcrystalline Cellulose.Also can use the conventional Drug coating that uses in a kind of this area.The example of Drug coating comprises the polymkeric substance of vinylformic acid and/or methacrylic acid and/or their ester or multipolymer, zein, ethyl cellulose, ethyl cellulose succinate, and shellac.
The softening agent that is suitable for Drug coating is citrate and tartrate, glycerine and glyceryl ester or the different polyoxyethylene glycol of chain length.
Liquid composition is to prepare in water or the acceptable organic solvent of physiology such as ethanol and fatty alcohol as solution and suspension.
This composition of liquid medicine can further comprise sanitas such as potassium solvate, 4-methyl hydroxybenzoate and 4-nipasol; Antioxidant such as xitix; And perfume compound such as spearmint oil.
In addition, can use conventional solubilizing agent or emulsifying agent during the obtaining liq pharmaceutical composition, as polyvinylpyrrolidone and polysolvate 80.
The vehicle that other is fit to and the example of assistant agent are open in doctor's H.P.Fielder " Lexikon derHilfsstoffe fur Pharmazie; Kosmetik und angrenzende Gebiete[Encyclopaediaof auxiliaries for pharmacy, cosmetics and related fields] ".
To the present invention be described in more detail by embodiment below.Therefore but the following embodiment that provides only is an illustrative, the invention is not restricted to these embodiment or is not subjected to the restriction of these embodiment.
Embodiment 1
3-fluoro-4-methylthio group oil of mirbane
Formula 7
With 8g 3, the 4-difluoro nitrobenzene is dissolved among the 50ml THF, to wherein adding 5g sulfo-sodium methylate, stirs 10 minutes, to wherein slowly adding 5ml DMF, stirs at ambient temperature 6 hours then.With 200ml water diluted reaction mixture, obtain faint yellow solid, with its filtration, and, obtain the 10.0g titled reference compound with cold ethanol and water washing, it is faint yellow solid (productive rate 88%).
1H-NMR(400MHz，CDCl
3)δ2.50(s，3H)，7.29(td，1H，7.5，8.6Hz)，7.87(dd，1H，J＝9.8，2.3Hz)，8.12(ddd，1H，J＝8.6，2.3，0.7Hz)
Embodiment 2
3-fluoro-4-methylthio group phenyl amine
Formula 8
3-fluoro-4-methylthio group oil of mirbane, 0.1eq Pd/C (5wt%), the 4eq ammonium formiate of 10.0g embodiment 1 preparation are dissolved among the THF/MeOH (1: 1), refluxed 3 hours.Filter out the solid that is not dissolved in this solution, and under reduced pressure distill filtrate, obtain oily compound, it is dissolved in the 80ml ethyl acetate again.Filter out the solid formic acid ammonium that is not dissolved in this solution, and under reduced pressure distill filtrate, obtain oily filtrate, its by column chromatography (ethyl acetate: purifying n-hexane=1: 3), obtain the 6.04g titled reference compound, it is yellow solid (productive rate 88%).
1H-NMR(400MHz，CDCl
3)δ3.01(s，3H)，6.59(td，1H，7.5，8.6Hz)，6.72(dd，1H，J＝9.8，2.3Hz)，7.54(ddd，1H，J＝8.6，2.3，0.7Hz)
Embodiment 3
3-fluoro-4-methylthio group phenyl hydrazonium salt hydrochlorate
Formula 9
Under-10 ℃, with in the foregoing description 2 preparation 3.8g 3-fluoro-4-methylthio group phenyl amine solvent in the dense HCl of 30ml, slow 1.5eq Sodium Nitrite in wherein being added in 20ml water, and under this temperature, stirred 2 hours, then slowly to wherein being added in the tin chloride dihydrate of 3eq in the dense HCl of 30ml, under uniform temp, stirred 1 hour, stirred at ambient temperature 10 hours, by using TLC (ethyl acetate: identification reaction process n-hexane=1: 3).When reaction is finished, to pH9, stirred 30 minutes, to wherein adding 200mlTHF, restir 30 minutes with sodium hydroxide solution conditioned reaction mixture.Filter reaction mixture, filtrate extracts three times with 200ml water and THF.By anhydrous magnesium sulfate drying THF layer, distillation under reduced pressure obtains oily filtrate, subsequently it is used the 10ml acetic acid ethyl dissolution.In this solution, add 4N hydrochloric acid in the 2ml Zai diox then, and this solution is distilled in decompression down.Slowly form solid product to wherein adding the 100ml Virahol, subsequent filtration obtains the 2.30g titled reference compound, and it is lark solid (productive rate 62%).
Embodiment 4
N-(3-fluoro-4-methylthio group phenyl) trifluoro second hydrazone (acetamidrazone)
Formula 10
The 900mg 3-fluoro-4-methylthio group phenyl hydrazonium salt hydrochlorate of preparation in the foregoing description 3 is dissolved in 40ml mixing solutions (MeOH: THF=1: 1), dropwise add the 0.80ml triethylamine to it, stirred this mixture 30 minutes.To wherein dropwise adding 910mg trifluoro ethanamidine (acetimidine) (85%), stirred at ambient temperature 24 hours.When reaction is finished,,, then once, and, under reduced pressure filter by anhydrous magnesium sulfate drying with saturated nacl aqueous solution washing organic layer with ethyl acetate extraction water layer twice to wherein adding entry and ethyl acetate.(ethyl acetate: the product that obtains of purifying n-hexane=1: 4) obtains the liquid titled reference compound of 700mg (productive rate 67%) by column chromatography.
1H-NMR(400MHz，DMSO-d6)δ2.40(s，3H)，6.50(s，2H)，6.60-6.70(m，1H)，7.25(t，2H，J＝8.4Hz)，8.75(s，1H)
Embodiment 5
3-fluoro-4-methylsulfonyl oil of mirbane
Formula 11
With 8g 3,4-difluoro nitrobenzene and 1.01eq methyl-sulfinic acid sodium (95%) are dissolved among the 10mol DMSO.Stirred 3 hours down at 60 ℃.When reaction is finished, in this solution, add 100ml water, form the lark solid, subsequent filtration is used 50ml cold water and 30ml n-hexane wash respectively, obtains the 8.8g titled reference compound, and it is lark solid (productive rate 79%).
Mass (low E1)=219.0
Embodiment 6
3-fluoro-4-methylsulfonyl phenyl amine
Formula 12
Replace 3-fluoro-4-methylthio group oil of mirbane except using 10.0g 3-fluoro-4-methylsulfonyl oil of mirbane, according to embodiment 2 in identical mode prepare the liquid titled reference compound of 6.04g (productive rate 70%).
Mass (low E1)=184.1 (M+)
Embodiment 7
3-fluoro-4-methylsulfonyl phenyl hydrazine hydrochloride
Formula 13
Replace 3-fluoro-4-methylthio group phenyl amine except using 3.5g 3-fluoro-4-methylsulfonyl phenyl amine, according to embodiment 3 in identical mode prepare the titled reference compound of 2.30g (productive rate 62%) solid state.
Embodiment 8
N-(3-fluoro-4-methylsulfonyl phenyl) trifluoro second hydrazone
Formula 14
Replace 3-fluoro-4-methylthio group phenyl hydrazonium salt hydrochlorate except using 900mg 3-fluoro-4-methylsulfonyl phenyl hydrazine hydrochloride, according to embodiment 4 in identical mode prepare the titled reference compound of 340mg (productive rate 34%) solid state.
1H-NMR(400MHz，DMSO-d6)δ3.12(s，3H)，6.85-7.00(m，3H)，7.75(t，2H，J＝8.5Hz)，9.35(s，1H)。
Embodiment 9
1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 15
200mg N-(3-fluoro-4-methylthio group phenyl) trifluoro second hydrazone is dissolved in 5ml 1, in the 4-diox, to wherein dropwise adding the 0.06ml pyridine.Reaction mixture was stirred 10 minutes at ambient temperature, then to wherein adding the 110mg Benzoyl chloride.Reaction mixture refluxed is 12 hours under its boiling point.When reaction finishes, reaction mixture is cooled to envrionment temperature, then to wherein adding entry and ethyl acetate.With ethyl acetate extraction water layer twice, the organic layer that obtains with saturated nacl aqueous solution washing once by anhydrous magnesium sulfate drying, and under reduced pressure filters then.By column chromatography (ethyl acetate: n-hexane=1; 4) product that obtains of purifying obtains the liquid titled reference compound of 170mg (productive rate 65%).
Embodiment 10
1-(3-fluoro-4-methylthio group phenyl)-5-(4-p-methoxy-phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 16
Replace Benzoyl chloride except using 120mg 4-methoxy benzoyl chloride, according to embodiment 9 in identical mode prepare the liquid titled reference compound of 200mg (productive rate 70%).
Embodiment 11
1-(3-fluoro-4-methylthio group phenyl)-5-(4-fluorophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 17
Replace Benzoyl chloride except using 120mg 4-fluorobenzoyl chloride, according to embodiment 9 in identical mode prepare the liquid titled reference compound of 166mg (productive rate 60%).
Embodiment 12
1-(3-fluoro-4-methylthio group phenyl)-5-(4-bromophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 18
Replace Benzoyl chloride except using 130mg 4-bromo-benzoyl chloride, according to embodiment 9 in identical mode prepare the liquid titled reference compound of 209mg (productive rate 65%).
Embodiment 13
1-(3-fluoro-4-methylthio group phenyl)-5-(4-chloro-phenyl-)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 19
Replace Benzoyl chloride except using 120mg 4-chloro-benzoyl chloride, according to embodiment 9 in identical mode prepare the liquid titled reference compound of 200mg (productive rate 68%).
Embodiment 14
1-(3-fluoro-4-methylthio group phenyl)-5-(4-aminomethyl phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 20
Replace Benzoyl chloride except using 125mg 4-methyl benzoyl chloride, according to embodiment 9 in identical mode prepare the liquid titled reference compound of 158mg (productive rate 58%).
Embodiment 15
1-(3-fluoro-4-methylthio group phenyl)-5-(4-ethoxyl phenenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 21
Replace Benzoyl chloride except using 115mg 4-ethoxy benzoyl chloride, according to embodiment 9 in identical mode prepare the liquid titled reference compound of 196mg (productive rate 66%).
Embodiment 16
1-(3-fluoro-4-methylthio group phenyl)-5-(3-chloro-phenyl-)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 22
Replace Benzoyl chloride except using 115mg 3-chloro-benzoyl chloride, according to embodiment 9 in identical mode prepare the liquid titled reference compound of 192mg (productive rate 66%).
Embodiment 17
1-(3-fluoro-4-methylthio group phenyl)-5-(3-fluorophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 23
Replace Benzoyl chloride except using 110mg 3-fluorobenzoyl chloride, according to embodiment 9 in identical mode prepare the liquid titled reference compound of 189mg (productive rate 68%).
Embodiment 18
1-(3-fluoro-4-methylthio group phenyl)-5-(3-fluoro-4-p-methoxy-phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 24
Replace Benzoyl chloride except using 120mg 3-fluoro-4-methoxy benzoyl chloride, according to embodiment 9 in identical mode prepare the liquid titled reference compound of 181mg (productive rate 61%).
Embodiment 19
1-(3-fluoro-4-methylthio group phenyl)-5-(3-aminomethyl phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 25
Replace Benzoyl chloride except using 115mg 3-methyl benzoyl chloride, according to embodiment 9 in identical mode prepare the liquid titled reference compound of 185mg (productive rate 71%).
Embodiment 20
1-(3-fluoro-4-methylthio group phenyl)-5-(naphthalene-2-yl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 26
Replace Benzoyl chloride except using 140mg naphthalene-2-dicarbonyl chloride, according to embodiment 9 in identical mode prepare the liquid titled reference compound of 196mg (productive rate 65%).
Embodiment 21
5-([1,3] benzo dioxole-5-yl)-1-(3-fluoro-4-methylthio group phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 27
Except using 140mg[1,3] benzo dioxole-5-dicarbonyl chloride replaces Benzoyl chloride, according to embodiment 9 in identical mode prepare the liquid titled reference compound of 172mg (productive rate 58%).
Embodiment 22
1-(3-fluoro-4-methylsulfonyl phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 28
With 150mg 1-(3-fluoro-4-methylthio group the phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1 of preparation in the foregoing description 9,2, the 4-triazole is dissolved in the mixed solvent (5ml methylene dichloride, 1ml methyl alcohol), to wherein slowly adding 350mg MMPP.Stirred this reaction mixture 5 hours and filtration, filtrate is washed once with sodium bicarbonate and saturated nacl aqueous solution respectively, by anhydrous magnesium sulfate drying, under reduced pressure filters then.(ethyl acetate: the product that obtains of purifying n-hexane=2: 3) obtains 139mg solid state titled reference compound (productive rate 88%) by column chromatography.
1H-NMR(400MHz，CDCl
3)δ3.20(s，3H)，7.20-7.50(m，6H)，8.05(m，1H)，8.15(m，1H)
Embodiment 23
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-p-methoxy-phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 29
Except using 1-(3-fluoro-4-methylthio group phenyl)-5-(4-the p-methoxy-phenyl)-3-Trifluoromethyl-1 H-1 of preparation among the 120mg embodiment 10,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the liquid titled reference compound of 90mg (productive rate 70%).
1H-NMR(400MHz，CDCl
3)δ3.20(s，3H)，3.90(s，3H)，6.80(d，2H，J＝8.4Hz)，7.35(m，1H)，7.45(d，2H，J＝8.4Hz)，8.05(m，1H)，8.15(m，1H)
Embodiment 24
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-fluorophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 30
Except using 1-(3-fluoro-4-methylthio group phenyl)-5-(4-the fluorophenyl)-3-Trifluoromethyl-1 H-1 of preparation among the 150mg embodiment 11,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the liquid titled reference compound of 125mg (productive rate 77%).
1H-NMR(400MHz，CDCl
3)δ3.20(s，3H)，7.00(dd，2H，J＝8.5，8.7Hz)，7.30-7.36(m，1H)，7.45(dd，1H，J＝2.0，9.7Hz)，7.50-7.60(m，2H)，8.05(dd，1H，J＝7.4，8.4Hz)
Embodiment 25
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-bromophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 31
Except using 1-(3-fluoro-4-methylthio group phenyl)-5-(4-the bromophenyl)-3-Trifluoromethyl-1 H-1 of preparation among the 150mg embodiment 12,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the titled reference compound of 142mg (productive rate 88%) solid state.
1H-NMR(400MHz，CDCl
3)δ3.20(s，3H)，7.20(dd，1H，J＝7.0，1.9Hz)，7.40(d，2H，J＝6.9Hz)，7.50-7.65(m，3H)，8.05(dd，1H，J＝7.4，8.4Hz)
Embodiment 26
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-chloro-phenyl-)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 32
Except using 1-(3-fluoro-4-methylthio group phenyl)-5-(4-the chloro-phenyl-)-3-Trifluoromethyl-1 H-1 of preparation among the 120mg embodiment 13,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the liquid titled reference compound of 113mg (productive rate 87%).
1H-NMR(400MHz，CDCl
3)δ3.20(s，3H)，7.20(d，1H，J＝8.0Hz)，7.40-7.60(m，5H)，8.00(dd，1H，J＝8.5，8.5Hz)
Embodiment 27
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-aminomethyl phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 33
Except using 1-(3-fluoro-4-methylthio group phenyl)-5-(4-the aminomethyl phenyl)-3-Trifluoromethyl-1 H-1 of preparation among the 120mg embodiment 14,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the titled reference compound of 100mg (productive rate 77%) solid state.
1H-NMR(400MHz，CDCl
3)δ2.30(s，3H)，3.20(s，3H)，7.10-7.20(m，3H)，7.40-7.55(m，3H)，8.00(dd，1H，J＝8.5，8.5Hz)
Embodiment 28
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-ethoxyl phenenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 34
Except using 1-(3-fluoro-4-methylthio group phenyl)-5-(4-the ethoxyl phenenyl)-3-Trifluoromethyl-1 H-1 of preparation among the 100mg embodiment 15,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the liquid titled reference compound of 86mg (productive rate 80%).
1H-NMR(400MHz，CDCl
3)δ1.50(t，3H，J＝6.9Hz)，3.20(s，3H)，4.10(q，2H，J＝6.9Hz)，6.80(d，2H，J＝9.6Hz)，7.25(dd，1H，J＝2.0，0.7Hz)，7.40(dd，1H，J＝2.0，7.0Hz)，7.90(dd，1H，J＝7.0 8.5Hz)，8.10(d，2H，J＝9.6Hz)
Embodiment 29
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3-chloro-phenyl-)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 35
Except using 1-(3-fluoro-4-methylthio group phenyl)-5-(3-the chloro-phenyl-)-3-Trifluoromethyl-1 H-1 of preparation among the 120mg embodiment 16,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the liquid titled reference compound of 110mg (productive rate 84%).
1H-NMR(400MHz，CDCl
3)δ3.20(s，3H)，7.00-7.55(m，5H)，8.00(m，1H)，8.05(m，1H)
Embodiment 30
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3-fluorophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 36
Except using 1-(3-fluoro-4-methylthio group phenyl)-5-(3-the fluorophenyl)-3-Trifluoromethyl-1 H-1 of preparation among the 150mg embodiment 17,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the liquid titled reference compound of 125mg (productive rate 77%).
1H-NMR(400MHz，CDCl
3)δ3.20(s，3H)，7.10-7.55(m，5H)，8.05(m，1H)，8.15(m，1H)
Embodiment 31
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3-fluoro-4-p-methoxy-phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 37
Except using 1-(3-fluoro-4-methylthio group phenyl)-5-(3-fluoro-4-the p-methoxy-phenyl)-3-Trifluoromethyl-1 H-1 of preparation among the 120mg embodiment 18,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the liquid titled reference compound of 125mg (productive rate 77%).
1H-NMR(400MHz，CDCl
3)δ3.20(s，3H)，3.80(s，3H)7.15-22(m，2H)，7.30(dd，1H，J＝1.8，12.9Hz)，7.35(m，1H)，8.05(m，1H)，8.15(m，1H)
Embodiment 32
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3-aminomethyl phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 38
Except using 1-(3-fluoro-4-methylthio group phenyl)-5-(3-the aminomethyl phenyl)-3-Trifluoromethyl-1 H-1 of preparation among the 120mg embodiment 19,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the liquid titled reference compound of 96mg (productive rate 75%).
1H-NMR(400MHz，CDCl
3)δ2.30(s，3H)，3.30(s，3H)，7.10-7.60(m，6H)，8.00(dd，1H，J＝8.5，8.5Hz)
Embodiment 33
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(naphthalene-2-yl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 39
Except using 1-(3-fluoro-4-methylthio group phenyl)-5-(naphthalene-2-the yl)-3-Trifluoromethyl-1 H-1 of preparation among the 120mg embodiment 20,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the liquid titled reference compound of 125mg (productive rate 77%).
1H-NMR(400MHz，CDCl
3)δ3.20(s，3H)，7.35(ddd，1H，J＝7.0，1.9，0.7Hz)，7.40(dd，1H，J＝8.7，1.8Hz)，7.50(dd，1H，J＝9.7，1.8Hz)，7.55-7.65(m，2H)，7.85-7.95(m，3H)，8.05(dd，1H，J＝7.4，8.4Hz)，8.20(dd，1H，J＝0.6，0.9Hz)
Embodiment 34
5-([1,3] benzo dioxole-5-yl)-1-(3-fluoro-4-methylsulfonyl phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 40
Except using the 5-([1 of preparation among the 120mg embodiment 21,3] benzo dioxole-5-yl)-1-(3-fluoro-4-methylthio group phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the liquid titled reference compound of 125mg (productive rate 77%).
1H-NMR(400MHz，CDCl
3)δ3.20(s，3H)，6.0(s，2H)，6.80(s，1H)，7.10(d，1H，J＝8.1Hz)，7.40(d，1H，J＝8.1Hz)，7.35(m，1H)，8.05(m，1H)，8.15(m，1H)
Embodiment 35
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3, the 4-difluorophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole
Formula 41
Except using 120mg 1-(3-fluoro-4-methylthio group phenyl)-5-(3, the 4-difluorophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole replaces 1-(3-fluoro-4-methylthio group phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole, according to embodiment 22 in identical mode prepare the liquid titled reference compound of 35mg (productive rate 27%).
1H-NMR(400MHz，CDCl
3)δ3.20(s，3H)，7.15-7.45(m，4H)，8.05(m，1H)，8.15(m，1H)
Experiment
1.
Selective COX-2-2 suppresses active evaluation
1)
Method
Measure selective COX-2-2 for pharmacology and suppress active, with the inhibition percentage ratio of the compound of the present invention that exemplifies among the following method measurement embodiment COX-1 and COX-2.
A.
Use U-937 to detect COX-1 and suppress active
Cultivate and centrifugation U-937 human lymphoma cell (Korea S's cell bank, Seoul, South Korea, accession designation number: 21593).The cell of collecting is 1 * 10 with HBSS dilution (* 1, the Hank balanced salt solution) to concentration
6Cells/ml.In each hole of 12-orifice plate, put into the cell solution of 1ml dilution.In the hole, add 1 μ M solution and 5 μ l in contrast the DMSOs of 5 μ l test compounds in DMSO.With this orifice plate at CO
2Cultivated 15 minutes for 37 ℃ in the incubator.Respectively, the arachidonic acid solution that the 10mM storing solution of arachidonic acid in ethanol is prepared 1mM with ten times of alcohol dilutions.Arachidonic acid plays substrate.The 1mM arachidonic acid solution that adds 10 μ l in each hole is at CO
2Cultivated 30 minutes for 37 ℃ in the incubator.Cell solution in each hole is put into the test tube of separating centrifuge, 4 ℃ with 10, the rotating speed centrifugation of 000rpm 5 minutes.In the cell of collecting with mono-clonal reagent set box (Cayman Chemicals) quantitative assay and the PGE2 concentration in the supernatant liquor.Calculate the PGE2 inhibition percentage ratio of the groups of cells of test compounds processing with respect to the groups of cells of DMSO processing.With this calculated value is the inhibition activity of basic evaluation COX-1.
B.
Use the inhibition activity of RAW 264.7 clones test COX-2
With 2 * 10
6(accession designation number: cell inoculation 40071) is in each hole of 12-orifice plate for Korea S's cell bank, Seoul, South Korea for individual RAW 264.7 clones.Each hole is handled with 250 μ M acetylsalicylic acid and was cultivated 2 hours at 37 ℃.After this developing medium is replaced with new substratum, this new substratum usefulness test compounds (10nM) processing and incubation 30 minutes.(LPS 100ng/ml) handles and cultivates 18 hours for each hole usefulness interferon-gamma (100 units per ml) and lipopolysaccharides then.This media transfer in other test tube, is used the concentration of EIA test kit (Cayman Chemicals) quantitative assay PGE2.
2)
Test result
Test result is shown in the table 1 hereinafter.Calculate COX according to following equation and suppress percentage ratio:
% suppresses=(concentration of PGE2 in the sample of the concentration of PGE2 in the test compounds untreated sample-test compounds processing)/(concentration of PGE2 in the test compounds untreated sample) * 100
Table 1
Inhibition (%) to cyclo-oxygenase (COX)
| Sample | COX-1(1μM) | COX-2(10nM) |
| Object of reference (Valdecoxib) | 28.8 | 5.47 |
| Embodiment 22 | 32.8 | 13.7 |
| Embodiment 23 | 15.5 | 41.2 |
| Embodiment 24 | 18.8 | 18.5 |
| Embodiment 25 | 19.5 | 13.7 |
| Embodiment 26 | 27.4 | 22.3 |
| Embodiment 27 | 26.4 | 19.0 |
| Embodiment 28 | 25.7 | 15.6 |
| Embodiment 29 | 11.1 | 16.4 |
| Embodiment 30 | 23.2 | 15.1 |
| Embodiment 31 | 26.4 | 16.2 |
| Embodiment 32 | 23.2 | 27.8 |
| Embodiment 33 | 44.5 | 13.5 |
| Embodiment 34 | 11.2 | 41.5 |
| Embodiment 35 | 21.2 | 15.5 |
3) estimate
Vitro test about COX-1 and COX-2 inhibition percentage ratio the results are shown in table 1.
As shown in table 1, COX-2 is significantly higher than the value of object of reference Valdecoxib among the embodiment 22-35 for inhibition (%) ratio of COX-1.This COX-2 that shows The compounds of this invention suppresses to be better than object of reference with respect to the selectivity of COX-1.
The compound exhibits of embodiment 22-35 goes out the inhibition activity to COX-2 apparently higher than object of reference.Based on this result, can see that compound of the present invention has the side effect of reduction, has relatively improved the effect that alleviates fever, pain and inflammation with object of reference owing to optionally improve.
Industrial usability
By above-mentioned apparent, the invention provides 1,2,4-triazole derivative or its non-malicious salt, its preparation method and comprise this derivative or salt as the pharmaceutical composition of activeconstituents.This pharmaceutical composition can alleviate fever, pain and inflammation effectively.Particularly because reduced the result of conventional non-steroid class anti-inflammatory agent side effect, this pharmaceutical composition is of value to the patient that treatment suffers from ulcer of digestive system disease, gastritis, regional ileitis, ulcerative colitis, diverticulitis, gastrorrhagia or hypoprothrombinemia.
Though the present invention has been carried out concrete displaying and explanation with reference to embodiment of the present invention, those of ordinary skill in the art will understand under the prerequisite of the spirit and scope of the present invention that define in not deviating from following claim, can make various changes on form and content to the present invention.
Claims (9)
1. one kind by 1,2 of formula 1 expression, 4-triazole derivative or its non-toxic salt:
Formula 1
Wherein:
Ar represents naphthyl; 3, the 4-methylenedioxyphenyl; Phenyl; Or quilt is selected from C
1-C
6Alkyl, C
1-C
6The phenyl that the group of alkoxyl group or halogen replaces.
2. according to 1,2 of claim 1,4-triazole derivative or its non-toxic salt, it is selected from:
1-(3-fluoro-4-methylsulfonyl phenyl)-5-phenyl-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-p-methoxy-phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-fluorophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-bromophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-chloro-phenyl-)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-aminomethyl phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(4-ethoxyl phenenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3-chloro-phenyl-)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3-fluorophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3-fluoro-4-p-methoxy-phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3-aminomethyl phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(naphthalene-2-yl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole;
5-([1,3] benzo dioxole-5-yl)-1-(3-fluoro-4-methylsulfonyl phenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole; With
1-(3-fluoro-4-methylsulfonyl phenyl)-5-(3, the 4-difluorophenyl)-3-Trifluoromethyl-1 H-1,2, the 4-triazole.
3. by the 1,2,4-triazol derivatives of formula 2 expression
Formula 2
Wherein, n is 0 or 2.
4. 1,2 of formula 1, the preparation method of 4-triazole derivative or its non-toxic salt comprises the 1,2,4-triazol derivatives of formula 2a and the acyl chlorides of formula 3 is reacted in the presence of alkali:
Formula 1
Formula 2a
Formula 3
Wherein, Ar as defined in claim 1.
5. 1,2 of formula 1, the preparation method of 4-triazole derivative or its non-toxic salt comprises the 1,2,4-triazol derivatives of formula 2b and the acyl chlorides of formula 3 is reacted in the presence of alkali, then the compound that obtains of oxidation:
Formula 1
Formula 2b
Formula 3
Wherein, Ar as defined in claim 1.
6. the preparation method of the 1,2,4-triazol derivatives of formula 2 comprises the hydrazine derivative of formula 4 and the trifluoro ethanamidine of formula 5 is reacted in the presence of alkali:
Formula 2
Formula 4
Formula 5
Wherein, n is 0 or 2.
7. pharmaceutical composition for the treatment of heating, pain and inflammation, it contains 1,2 of the claim 1 for the treatment of significant quantity or 2, and 4-triazole derivative or its non-toxic salt are as activeconstituents and drug acceptable carrier.
8. pharmaceutical composition for the treatment of cancer, it contains 1,2 of the claim 1 for the treatment of significant quantity or 2, and 4-triazole derivative or its non-toxic salt are as activeconstituents and drug acceptable carrier.
9. treat dull-witted pharmaceutical composition for one kind, it contains 1,2 of the claim 1 for the treatment of significant quantity or 2, and 4-triazole derivative or its non-toxic salt are as activeconstituents and drug acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2002-0072688A KR100470075B1 (en) | 2002-11-21 | 2002-11-21 | 1,2,4-triazole derivatives, processes for the preparation thereof, and pharmaceutical compositions containing the same |
| KR1020020072688 | 2002-11-21 |
Publications (2)
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| CN1717397A true CN1717397A (en) | 2006-01-04 |
| CN100355738C CN100355738C (en) | 2007-12-19 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CNB038256940A Expired - Fee Related CN100355738C (en) | 2002-11-21 | 2003-07-29 | 1,2,4-triazole derivative, method for preparing the same, and pharmaceutical composition containing the same |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US6849652B1 (en) |
| EP (1) | EP1567508B1 (en) |
| JP (1) | JP4348300B2 (en) |
| KR (1) | KR100470075B1 (en) |
| CN (1) | CN100355738C (en) |
| AT (1) | ATE497497T1 (en) |
| AU (1) | AU2003256091A1 (en) |
| DE (1) | DE60335960D1 (en) |
| ES (1) | ES2357834T3 (en) |
| WO (1) | WO2004046121A1 (en) |
Families Citing this family (5)
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|---|---|---|---|---|
| KR100491317B1 (en) * | 2002-11-26 | 2005-05-24 | 씨제이 주식회사 | 1,2,4-Triazole derivatives, processes for the preparation thereof, and pharmaceutical compositions containing the same |
| KR100470076B1 (en) * | 2002-11-27 | 2005-02-05 | 씨제이 주식회사 | 1,2,4-triazole derivatives, processes for the preparation thereof, and pharmaceutical compositions containing the same |
| AR044503A1 (en) * | 2003-03-18 | 2005-09-14 | Merck & Co Inc | TRIAZOLS REPLACED WITH BIARILO AS BLOCKERS OF THE SODIUM CHANNEL |
| KR100576343B1 (en) * | 2004-07-22 | 2006-05-03 | 씨제이 주식회사 | 1,2,4-Triazole derivatives, processes for the preparation thereof, and pharmaceutical compositions containing the same |
| WO2008033466A2 (en) * | 2006-09-14 | 2008-03-20 | Combinatorx (Singapore) Pre. Ltd. | Compositions and methods for treatment of viral diseases |
Family Cites Families (13)
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|---|---|---|---|---|
| US4075341A (en) * | 1974-05-24 | 1978-02-21 | Gruppo Lepetit S.P.A. | 2-Substituted phenyl-5-triazols [5,1-a] isoquinoline compounds |
| US4259504A (en) * | 1979-08-27 | 1981-03-31 | American Cyanamid Company | Substituted 1H-1,2,4-triazoles |
| EP0051084A1 (en) * | 1980-11-04 | 1982-05-12 | American Cyanamid Company | Substituted 1H-1,2,4-triazoles |
| DE4240587A1 (en) * | 1992-12-03 | 1994-06-09 | Bayer Ag | Prepn of aromatic polycarbonate from di:phenol and di:aryl carbonate, in melt - in presence of catalyst, with passage of large current of inert gas through melt |
| US5474995A (en) | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
| US5466823A (en) * | 1993-11-30 | 1995-11-14 | G.D. Searle & Co. | Substituted pyrazolyl benzenesulfonamides |
| US5434178A (en) * | 1993-11-30 | 1995-07-18 | G.D. Searle & Co. | 1,3,5 trisubstituted pyrazole compounds for treatment of inflammation |
| US5908852A (en) * | 1994-11-14 | 1999-06-01 | G. D. Searle & Co. | 1,3,5 trisubstituted pyrazole compounds for treatment of inflammation |
| US5633272A (en) | 1995-02-13 | 1997-05-27 | Talley; John J. | Substituted isoxazoles for the treatment of inflammation |
| WO2000010564A1 (en) * | 1998-08-21 | 2000-03-02 | Competitive Technologies, Inc. | 4-amino-3-mercapto-1,2,4-triazoles |
| EP1099695A1 (en) * | 1999-11-09 | 2001-05-16 | Laboratoire Theramex S.A. | 5-aryl-1H-1,2,4-triazole compounds as inhibitors of cyclooxygenase-2 and pharmaceutical compositions containing them |
| US6451820B1 (en) * | 2000-03-23 | 2002-09-17 | Boehringer Ingelheim Pharmaceuticals, Inc. | Substituted 1-(4-aminophenly)triazoles and their use as anti-inflammatory agents |
| DE10123586A1 (en) * | 2001-05-08 | 2002-11-28 | Schering Ag | New 3,5-diamino-1,2,4-triazole derivatives, are cyclin dependent kinase inhibitors useful for treating e.g. cancer, autoimmune, cardiovascular or neurodegenerative diseases or viral infections |
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2002
- 2002-11-21 KR KR10-2002-0072688A patent/KR100470075B1/en not_active IP Right Cessation
-
2003
- 2003-07-29 EP EP03811548A patent/EP1567508B1/en not_active Expired - Lifetime
- 2003-07-29 AT AT03811548T patent/ATE497497T1/en not_active IP Right Cessation
- 2003-07-29 DE DE60335960T patent/DE60335960D1/en not_active Expired - Lifetime
- 2003-07-29 ES ES03811548T patent/ES2357834T3/en not_active Expired - Lifetime
- 2003-07-29 CN CNB038256940A patent/CN100355738C/en not_active Expired - Fee Related
- 2003-07-29 JP JP2004553243A patent/JP4348300B2/en not_active Expired - Fee Related
- 2003-07-29 AU AU2003256091A patent/AU2003256091A1/en not_active Abandoned
- 2003-07-29 WO PCT/KR2003/001514 patent/WO2004046121A1/en active Application Filing
- 2003-07-31 US US10/631,594 patent/US6849652B1/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US6849652B1 (en) | 2005-02-01 |
| DE60335960D1 (en) | 2011-03-17 |
| EP1567508B1 (en) | 2011-02-02 |
| EP1567508A1 (en) | 2005-08-31 |
| CN100355738C (en) | 2007-12-19 |
| JP2006514631A (en) | 2006-05-11 |
| JP4348300B2 (en) | 2009-10-21 |
| EP1567508A4 (en) | 2008-12-10 |
| AU2003256091A1 (en) | 2004-06-15 |
| ES2357834T3 (en) | 2011-05-03 |
| WO2004046121A1 (en) | 2004-06-03 |
| KR20040044614A (en) | 2004-05-31 |
| ATE497497T1 (en) | 2011-02-15 |
| KR100470075B1 (en) | 2005-02-05 |
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